Primate erythrocytes, or red blood cells (RBC's), play an essential role in the clearance of antigens from the circulatory system. The formation of an immune complex in the circulatory system activates the complement factor C3b in primates and leads to the binding of C3b to the immune complex. The C3b/immune complex then binds to the type 1 complement receptor (CR1), a C3b receptor, expressed on the surface of erythrocytes via the C3b molecule attached to the immune complex. The immune complex is then chaperoned by the erythrocyte to the reticuloendothelial system (RES) in the liver and spleen for neutralization. The RES cells, most notably the fixed-tissue macrophages in the liver called Kupffer cells, recognize the C3b/immune complex and break this complex from the RBC by severing the C3b receptor-RBC junction, producing a liberated erythrocyte and a C3b/immune complex which is then engulfed by the Kupffer cells and is completely destroyed within subcellular organelles of the Kupffer cells. This pathogen clearance process, however, is complement-dependent, i.e., confined to immune complexes recognized by the C3b receptor, and is ineffective in removing immune complexes which are not recognized by the C3b receptor.
Taylor et al. have discovered a complement independent method of removing pathogens from the circulatory system. Taylor et al. have shown that chemical crosslinking of a first monoclonal antibody (mAb) specific to a primate C3b receptor to a second monoclonal antibody specific to a pathogenic antigenic molecule creates a snare heteropolymeric antibody or snare heteropolymer (HP) which offers a mechanism for binding a pathogenic antigenic molecule to a primate's C3b receptor without complement activation (U.S. Pat. Nos. 5,487,890; 5,470,570; and 5,879,679). It was also shown that 7B7, a monoclonal antibody to the bacteriophage ΦX174, was capable of partially neutralizing the bacteriophage when it was cross-linked and presented as an HP, although 7B7 had no neutralizing activity in its monomeric form. Taylor et al., J. of Immunology, 158:842-850 (1997). Taylor also reported an HP which can be used to remove a pathogenic antigen specific auto antibody from the circulation. Such an HP, also referred to as an “Antigen-based Heteropolymer” (AHP), contains a CR1 specific monoclonal antibody cross-linked to an antigen (see, e.g., U.S. Pat. No. 5,879,679; Lindorfer et al., 2001, Immunol Rev. 183: 10-24; Lindorfer et al., 2001, J. Immunol Methods 248: 125-138; Ferguson et al., 1995, Arthritis Rheum 38: 190-200). HPs have been shown to induce rapid clearance of targets from the bloodstream. However, HPs are rapidly cleared via their Fc regions, and consequently would not be expected to persist long enough in circulation to effectively capture virus that is continuously emerging from tissues. Furthermore, because HPs use an antibody to capture the pathogen, they are serotype specific and may be readily avoided by surface antigen mutation of pathogens.
Soluble receptors have also been developed to reduce infection in animals. For example, Coxsackievirus and adenovirus receptor (CAR) synthesized as a soluble IgG1-Fc fusion protein (CAF-Fc) has been found to reduce coxsackievirus B3-mediated pancreatitis and myocarditis in mice (Yanagawa et al. 2004. J. Infect. Dis. 189:1431). However, these soluble receptors may not be completely effective and seem to operate at low efficiency in vivo.
The development of compositions that have long half-lives in vivo and that can reduce infection of target cells by pathogenic agents would be of great benefit.